A primary pathological component of Alzheimer's disease (AD) is brain inflammation. Activation of microglia, the "macrophages of the brain", is known to occur in AD and believed to contribute to the neuronal damage. Studies of peripheral macrophages have determined that multiple distinct activation states of macrophages exist, and recent studies have confirmed these findings in microglia. Macrophages/microglia can be broadly defined as being classically activated or alternatively activated. Classically activated macrophages are typified by the release of proinflammatory cytokines (e.g. IL-12, TNF-1) and reactive oxygen and nitrogen species, which are components of the inflammatory response that is known to cause neuronal damage. However, not all forms of microglia activation are detrimental. Some forms of microglia activation are beneficial, such as alternative activation responses that lead to removal or clearance of amyloid beta (A2). This proposal will test the hypothesis that the p381 MAP kinase signaling cascade leads to the detrimental forms of microglia activation, and that blocking the p381 pathway will decrease the detrimental responses of activated microglia without affecting the beneficial responses. Aim 1 will test the hypothesis that activation of the p381 MAP kinase signaling cascade occurs in microglia during the early phase of pathogenesis in an AD-relevant transgenic mouse model (the Tg6799 mouse). Aim 2 will use a novel, brain-penetrant, small molecule inhibitor of p381 to test the hypothesis that suppression of p381 activity will slow the pathology in the Tg6799 mouse. This aim will provide training in the use of pharmacological tools, transgenic models of neurodegenerative disease, and therapeutic target validation. Aim 3 will evaluate the relative contribution of p381 in microglia vs. other neural cell types in the damage produced by A2. To test this aim, we will use an A2 infusion AD-relevant model in a mouse with a genetic deletion of p381 only in the microglia. This aim will provide training in the use of conditional knockout mouse models using the cre/lox system, and stereotaxic surgery in mice. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p381 is involved in CNS pathophysiology mechanisms and intervention responses, and will form the foundation for follow-on CNS therapeutic development campaigns targeting this important protein kinase. A Career Development Plan has been formalized, and includes a combination of formal classroom and specialty workshop participation, regular presentations of proposed research plans and results at the laboratory and research group level, presentation of independent research results in seminar format, participation in national and international scientific meetings, preparation of research proposals and publications, and development of additional career- enhancing skills. An experienced mentor, a rich scientific environment, and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth, career enhancement and development into an independent academic investigator. PUBLIC HEALTH RELEVANCE: Neuroinflammation is increasingly being recognized as a contributor to pathology in many neurodegenerative diseases, such as Alzheimer's disease, a devastating disease of aging with no effective treatment or cure. Successful completion of this project will provide mechanistic insight into how the key regulatory protein, p381 MAPK, is involved in brain pro-inflammatory responses and CNS dysfunction caused by disease-relevant stressors. In addition, the results will delineate the relative importance of microglial p381 MAPK to the disease-relevant pathological responses. Longer term, the insights and knowledge generated by the proposed studies will provide a firmer foundation for future development of new classes of disease- modifying therapeutics and fuller interpretation of disease progression investigations.